Interests

MAJOR SCIENTIFIC ACHIEVEMENTS last 5 yearsPersonal Statement. I have been studying the cellular and physiological properties of astrocytes for about 20 years, and my laboratory and I have contributed significantly to extending our understanding of astrocyte-neuron interactions under physiological and pathological conditions, including the associated intra- and extra-cellular signalling events responsible for correct communications with other brain cell types [Bezzi et al., Nature, 1998; Bezzi et al., Nature Neurosci., 2001; Bezzi et al., Nature Neurosci., 2004; Marchaland et al., J of Neurosci., 2008; Prada et al., JCB,  2011; Buscemi et al., Cerebral Cortex, 2017; Petrelli et al., Mol Psy., 2018]. Total citations: 5694; H index 10: 38. For the past 10 years since I started my independent career, my research group has been focusing on the cellular, molecular and functional mechanisms regulating postnatal development of astrocytes. We are interested in exploring how astrocytes develop and how developmental dysfunctions could contribute to the pathophysiology of brain disorders.We are currently exploring fundamental aspects of astrocyte cell biology during postnatal development and some of our key areas of focus include:•     The role of astrocytes in the mechanisms underlying dendritic morphogenesis and synapse formation in the developing cortex;•     The contribution of astrocytes to the pathophysiology of neurodevelopmental disorders. For these studies we are using a combination of techniques including mouse genetics, in utero electroporation, molecular and cellular biology, advanced microscopy (SEM, confocal and two photon imaging, STED) and behavioral tests. Major Contribution to NeuroScience. Cellular mechanisms regulating dopamine homeostasis in the developing prefrontal cortex: role of astrocytes. In our last project we found a new role of astrocytes in the regulation of dopamine (DA) homeostasis in the developing prefrontal cortex (PFC) and thus, in the maturation of the associated cognitive functions.In mammals PFC, DA signaling supports higher-order cognitive functions and is dysregulated in many neuropsychiatric disorders, including schizophrenia and autism. In adult PFC, an appropriate background level of DA (i.e. DAergic tone) is controlled by homeostatic mechanisms that have been mainly ascribed to neurons, although decades of research have shown that astrocytes contain key enzyme for DA metabolism: i.e. mitochondrial enzyme monoamino oxidase B (MAOB). Moreover, many of DA specific actions on cognitive functions result from DA signals reaching receptors on remote extrasynaptic membranes via gradient diffusion (the so called volume transmission). The cell mechanisms regulating proper dopaminoception via volume transmission may be particularly crucial during development, when DA levels can have trophic effects on cortical development. How the notoriously fine DAergic tone is controlled in the developing cortex remains, to date, elusive.In our study we investigated a possible role of astrocytes in the homeostasis of brain monoamines and found, for the first time, that a subset of astrocytes during postnatal development of frontal and prefrontal cortex are endowed with unique features of “dopaminergic (DAergic) glial cells” insofar as they control DA homeostasis by expressing some of the core proteins for DA uptake, storage and metabolism (i.e. plasma membrane OCT3 transporter, vesicular transporter VMAT2 and metabolic enzymes MAOB).The ability of DAergic astrocytes to control DA homeostasis mainly depends on the presence of VMAT2. At the cellular level, astrocytic VMAT2 acts in concert with plasma membrane OCT3 to effectively control vesicular storage and metabolic capacity by pumping DA from the cytoplasm into intracellular organelles we have identified (i.e. late endosomes/lysosomes). Under normal conditions, astrocytic VMAT2 sequesters the majority of DA in the cytoplasm back into storage organelles, thus leaving the amount that escapes sequestration for metabolism. Bearing in mind that VMAT2-positive organelles are late endosomes/lysosomes that continuously undergo a cycle of transient contacts with each other, it is likely that DA stores exist in a highly dynamic state and that the passive outward leakage of DA is counter-balanced by active inward transport powered by VMAT2, thus allowing to tune the amount of DA metabolism (mainly by MAOB) to take place in the cytoplasm of astrocytes.Consistent with these findings, by using conditional gene inactivation and viral-mediated gene replacement in vivo we found that astroglial VMAT2 governs extracellular DA levels (i.e. DAergic tone) for adequate DA-dependent synaptic transmission and plasticity that mediate spines formation and maturation as well as efficient cognitive performances. Indeed, at the cellular levels in the absence of VMAT2, the dynamic equilibrium maintaining proper DA metabolism is lost, and the cytoplasmic DA taken up by the plasma membrane transporter is continuously metabolized by MAOB, thus creating an imbalance in extracellular levels. Deletion of astroglial VMAT2 and the associated decrease of DA are accompanied by robust cognitive phenotypes such as decreased executive functions (i.e. working memory and behavioral flexibility). The restoration of astrocyte VMAT2 or treatment with L-DOPA in the initial period of DA imbalance was sufficient to prevent the cognitive and behavioural deficiencies.Thus, by showing that astrocytes are integral component of the DAergic modulation in the developing brain, our study indicates for the first time that the homeostatic control of DA in the developing PFC represents a new mechanism by which astrocytes may influence neural circuit development. The region-specificity of this new role of astrocytes suggests, moreover, that these cells could be promising novel pharmacological target in neuropsychiatric disorders characterized by unbalanced PFC DAergic state. 1. Dysfunction of homeostatic control of dopamine by astrocytes in the developing prefrontal cortex leads to cognitive impairments.Petrelli F, Dallérac G, Pucci L, Calì C, Zehnder T, Sultan S, Lecca S, Chicca A, Ivanov A, Asensio CS, Gundersen V, Toni N, Knott GW, Magara F, Gertsch J, Kirchhoff F, Déglon N, Giros B, Edwards RH, Mothet JP, Bezzi P.Mol Psychiatry., 2018